Each year approximately 800,000 individuals in the USA suffer a stroke, with yearly direct and indirect societal costs that exceed $40 B. Stroke ranks third among all causes of death. Currently, only therapies that induce reperfusion of an ischemic brain are widely approved as treatments for acute stroke (e.g., thrombolysis with alteplase (tissue plasminogen activator or rt-PA). These balance improved overall outcome with the potential for serious complications and are underused. Safe pharmacological neuroprotection, brain salvage by enhancing the brain's resilience to ischemia, could dramatically enhance the number of patients that could benefit from acute stroke treatment. However, over decades, research has failed to translate over 1000 neuroprotective treatments from discovery in cells and rodents to utility in humans, and clinical trials of putative neuroprotectants have failed. This scientific crisis gave rise to a prevailing paradigm that pharmacological neuroprotection is not feasible or practicable in humans. Thus there is an urgent unmet need to determine whether or not neuroprotection in humans is possible.
Stroke can be the result of ischemia or hemorrhage. Hemorrhagic stroke accounts for about 17% of strokes but gives rise to a disproportionate share of deaths and debilitating injury. Hemorrhagic stroke is aggravated rather than alleviated by the only approved stroke drugs, such as tPA, which act to restore blood flow. Too often, the time required to bring a subject to a hospital, reach an initial diagnosis and perform a brain scan to distinguish between ischemic and hemorrhagic stroke would place a subject outside the window in which tPA can be effective. Thus, many ischemic stroke subjects, who could benefit from tPA, do not receive it.
Hemorrhage in or proximate to the CNS can also occur independently of ischemic stroke, particularly in subarachnoid hemorrhages, and dural or subdural hematoma and brain contusions. Such hemorrhages can arise as a result of physical trauma, such as a fall or other blow to the head or from shaken baby syndrome. Although the immediate symptoms of such hemorrhages can range from deceptively mild to severe, they can all rapidly become severe and life threatening. Such hemorrhages are thus a life-threatening emergency that even with the best current treatment often results in death or debilitating injury.
Subarachnoid Hemorrhage (SAH) is characterized by bleeding into the subarachnoid space. SAH is a serious, acute, life-threatening event that can result in chronic debilitation. In about 85% of cases of spontaneous SAH, the cause is the rupture of an intracranial aneurysm, termed aneurysmal SAH. Aneurysmal SAH most commonly affects people between the ages of 40 and 60 years, and is more likely to occur in women. The incidence of aneurysmal SAH is 10 in every 100,000 individuals per year in the U.S. Other less common causes of SAH include conditions such as vascular malformations. Acquired risk factors include high blood pressure, alcohol abuse, drug abuse, smoking, and contraceptive use. Other risk factors include aneurysm in other blood vessels, fibromuscular dysplasia and other connective tissue disorders, and history of polycystic kidney disease.
SAH is a multiphasic event, with an acute brain insult that occurs at the time of the initial bleed which is followed by secondary potentially injurious events such as ischemia that occur from cerebral vasospasm and hydrocephalus. In the acute SAH-induced injury, distribution of blood in the subarachnoid space, elevation of intracranial pressure (ICP), reduced cerebral perfusion pressure (CPP) and cerebral blood flow (CBF) initiate an acute injury cascade that produces transient brain ischemia, brain trauma due to the impulse produced by the sudden rise in ICP and, in some cases, brain injury due to intracerebral hematoma formation. Additionally, these initial events may lead to direct microvascular injury, plugging of vessels and release of vasoactive substances by platelet aggregates.
Secondary ischemic processes include anaerobic cellular respiration, energy depletion, impaired protein synthesis, excitotoxicity, free radical attack, neuronal stress, deoxyribonucleic acid (DNA) damage, apoptosis and necrosis, alterations in nitric oxide (NO)/nitric oxide synthase (NOS) pathways and lipid peroxidation. Although there is broad agreement about the range of secondary processes that may participate in producing brain injury following SAH, the precise contribution of individual mechanisms during the acute injury period remain incompletely understood.
Cerebral ischemia in SAH is the result of cerebral arterial vasospasm, and complicates the clinical course of approximately 30% of cases. The incidence of clinically-relevant vasospasm in SAH is highest between days 5 and 12 after the SAH. However, this complication is quite uncommon in the first three days after a SAH. A patient's ultimate clinical outcome after a SAH likely depends on the several factors, including demographic factors such as age and co-morbidities, the severity of the SAH, and the various complications of the SAH such as hydrocephalus and vasospasm. Thus, cerebral ischemia due to vasospasm is not the sole contributor to an adverse clinical outcome from SAH as symptoms appear immediately after rupture.
A different form of treatment for stroke and related conditions is now in clinical trials (see WO 2010144721 and Aarts et al., Science 298, 846-850 (2002)). This treatment uses TAT-NR2B9C, also known as Tat-NR2B9c (YGRKKRRQRRRKLSSIESDV; SEQ ID NO:6], an agent that inhibits PSD-95 binding to NMDAR 2 family members, thus reducing excitotoxicity induced by cerebral ischemia. Treatment has been reported to reduce infarction size and functional deficits in ischemic stroke and traumatic brain injuries.